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Type I interferons drive the maturation of human DC3s with a distinct costimulatory profile characterized by high
Melanie Girard1, Jaclyn C Law1, Maria I Edilova1
1Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Insights
Type I interferons (IFN-I) induce distinct responses in human immune cells. This study reveals how IFN-β specifically drives maturation in CD1c+ CD5- dendritic cell 3 (DC3) subsets, impacting T cell costimulation.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Human mononuclear phagocytes, including dendritic cells (DCs) and monocytes, have specialized subsets.
- The precise regulation of T cell costimulatory signals by these subsets in response to type I interferons (IFN-I) is not fully understood.
Purpose of the Study:
- To investigate the cell type-specific responses of human peripheral blood DC and monocyte subsets to IFN-I.
- To focus on the differential regulation of costimulatory molecules by these subsets.
Main Methods:
- Multiparameter flow cytometry
- CITE-sequencing
- Transcriptomic analysis
- Gene regulatory network analysis
Main Results:
- IFN-β drives maturation of the CD1c+ CD5- DC3 subset, increasing GITRL and decreasing CD86 expression compared to other DC subsets.
- DC3s exhibit an intermediate phenotype between DC2s and monocytes, with high MHCII, Fc receptors, and NADPH oxidase components.
- IFN-β elicits both shared and subset-specific responses, including differential costimulatory molecule expression, with NFKB1 driving DC3 maturation.
Conclusions:
- IFN-β induces distinct maturation programs in human DC and monocyte subsets.
- NF-κB activation is crucial for DC3 maturation upon IFN-β exposure.
- This study highlights the unique costimulatory potential of DC3 subsets in response to IFN-I.
Abstract:
Human mononuclear phagocytes comprise specialized subsets of dendritic cells (DCs) and monocytes, but how these subsets individually regulate expression of the molecular signals involved in T cell costimulation is incompletely understood. Here, we used multiparameter flow cytometry and CITE-sequencing to investigate the cell type-specific responses of human peripheral blood DC and monocyte subsets to type I interferons (IFN-I), focusing on differential regulation of costimulatory molecules. We report that IFN-β drives the maturation of the recently identified human CD1c+ CD5- DC3 subset into cells with higher GITRL and lower CD86 expression compared with other conventional DC subsets. Transcriptomic analysis confirmed that DC3s have an intermediate phenotype between that of CD1c+ CD5+ DC2s and CD14+ monocytes, characterized by high expression of MHCII, Fc receptors, and components of the phagocyte NADPH oxidase. IFN-β induced a shared core response in human DC and monocyte subsets as well as subset-specific responses, including differential expression of costimulatory molecules. Gene regulatory network analysis suggests that upon IFN-β stimulation NFKB1 drives DC3s to acquire a maturation program shared with DC2s. Accordingly, inhibition of NF-κB activation prevented the acquisition of a mature phenotype by DC3s upon IFN-β exposure. Collectively, this study provides insight into the cell type-specific response of human DC and monocyte subsets to IFN-I and highlights the distinct costimulatory potential of DC3s.
